ABSTRACT Heart failure (HF) is a major cause of morbidity and mortality in the United States. While progress in conventional treatments is making steady and incremental gains to reduce HF mortality, there is a critical need to explore new therapeutic approaches. Human and experimental models of HF revealed that a major defect in HF is the reduced expression and altered activity of the cardiac sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a). In fact, genetic overexpression of SERCA2a significantly rescued HF phenotypes and increased animal survival. Therefore, targeting dysfunctional SERCA2a with small molecule drugs that directly activate native SERCA2a pump is a persuasive strategy to treat HF. In this proposal, we aim to benchmark and test a newly discovered SERCA2 allosteric activator- CDN1163- in HF mouse models. CDN1163 directly binds to and triggers intrinsic activation of SERCA2a. Preliminary results in animal models of diabetes show significant improvement in cardiomyocyte contractility and cardiac dysfunction in vivo. We expect to: (1) Determine whether activation of SERCA2a correlates with a decrease in HF-associated contractile impairment; and (2) Identify a set of compounds suitable for further development as drugs to treat HF. In this Phase 1 SBIR application, we will use medicinal chemistry to optimize the potency, and develop the structure-activity relationships (SAR) of our most promising lead compounds based on contractile function in isolated myocytes in vitro, and functional testing in a rodent model of HF in vivo. Our goal in SUMOCOR LLC is to provide drug- like compounds suitable for development as novel therapeutic potential to treat HF.